Psoriasis is a debilitating and disfiguring skin disease affecting about 2% of the population. Existing treatments have significant side effects or, in the case of emerging biologics, are expensive and available only as systemic treatments that have to be injected and have potentially severe side-effects. Our goal is to develop RNA-based treatments that can be applied topically to inhibit specifically the expression of genes believed to be involved in the maintenance of psoriatic plaques. Topical treatment should be relatively free of side-effects and should require far lower amounts of drug and be easier for patients to self-administer than systemic treatments. In preliminary experiments, we have demonstrated dramatic knock-down of endogenous genes in the skin of living mice following intradermal injection of small hairpin RNAs (shRNAs). In this project, we will identify shRNAs targeting a key protein, Stat3, whose expression in keratinocytes has recently been convincingly implicated in psoriasis. These inhibitors will be tested for their ability to knock down Stat3 in cultured keratinocytes and in mouse skin. We will also test for the ability of these inhibitors to reverse the psoriasis-like features exhibited by a transgenic mouse that constitutively expresses Stat3, including epiderdermal hyperplasia. Identifying optimal methods for delivering the inhibitors to human skin will be a focus of Phase II of this SBIR project, but some topical formulations will be evaluated in Phase I along with the use of tape-stripping and/or intradermal injection to demonstrate proof of concept. This work will be collaboration with Dr. John DiGiovanni of M.D. Anderson Cancer Center, who discovered the Stat3-psoriasis connection. Psoriasis is a debilitating and disfiguring skin disease affecting about 2% of the population, and 10-30% of patients also have a form of the disease that affects the joints (psoriatic arthritis). Existing treatments have significant side effects cases or are very expensive and available only as systemic treatments that have risks of their own. Our goal is to treat affected skin with RNA-based drugs to inhibit the expression of genes known or suspected to be involved in the maintenance of psoriatic plaques. [unreadable] [unreadable] [unreadable]